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TitleBacPROTACs mediate targeted protein degradation in bacteria.
Journal, issue, pagesCell, Vol. 185, Issue 13, Page 2338-2353.e18, Year 2022
Publish dateJun 23, 2022
AuthorsFrancesca E Morreale / Stefan Kleine / Julia Leodolter / Sabryna Junker / David M Hoi / Stepan Ovchinnikov / Anastasia Okun / Juliane Kley / Robert Kurzbauer / Lukas Junk / Somraj Guha / David Podlesainski / Uli Kazmaier / Guido Boehmelt / Harald Weinstabl / Klaus Rumpel / Volker M Schmiedel / Markus Hartl / David Haselbach / Anton Meinhart / Markus Kaiser / Tim Clausen /
PubMed AbstractHijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis-targeting chimeras. Despite their great promise for medical chemistry, ...Hijacking the cellular protein degradation system offers unique opportunities for drug discovery, as exemplified by proteolysis-targeting chimeras. Despite their great promise for medical chemistry, so far, it has not been possible to reprogram the bacterial degradation machinery to interfere with microbial infections. Here, we develop small-molecule degraders, so-called BacPROTACs, that bind to the substrate receptor of the ClpC:ClpP protease, priming neo-substrates for degradation. In addition to their targeting function, BacPROTACs activate ClpC, transforming the resting unfoldase into its functional state. The induced higher-order oligomer was visualized by cryo-EM analysis, providing a structural snapshot of activated ClpC unfolding a protein substrate. Finally, drug susceptibility and degradation assays performed in mycobacteria demonstrate in vivo activity of BacPROTACs, allowing selective targeting of endogenous proteins via fusion to an established degron. In addition to guiding antibiotic discovery, the BacPROTAC technology presents a versatile research tool enabling the inducible degradation of bacterial proteins.
External linksCell / PubMed:35662409 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.68 - 10.0 Å
Structure data

11707

7abr

EMDB-11707, PDB-7abr:
Cryo-EM structure of B. subtilis ClpC (DWB mutant) hexamer bound to a substrate polypeptide
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-11708:
Cryo-EM map of the activated B. subtilis ClpC arranged as a tetramer of hexamers
Method: EM (single particle) / Resolution: 10.0 Å

PDB-7aa4:
Structure of ClpC1-NTD bound to a CymA analogue
Method: X-RAY DIFFRACTION / Resolution: 1.68 Å

Chemicals

ChemComp-HOH:
WATER

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

Source
  • Bacillus subtilis subsp. subtilis str. 168 (bacteria)
  • unidentified (others)
  • bacillus subtilis (strain 168) (bacteria)
  • mycobacterium tuberculosis (bacteria)
  • streptomyces (bacteria)
KeywordsCHAPERONE / helical receptor domain / cyclomarin A inhibtor / AAA+ protein / protein degradation

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